Pharmacological treatment of parkinson&#39;s disease

ABSTRACT

The present invention relates to the co-administration of two neurotransmitter agonists to patients with motor disorders, for the purpose of symptom reduction. In particular the present invention provides methods and compositions for alleviation of akinesia, rigidity and/or tremor associated with Parkinson&#39;s disease.

This application claims benefit of U.S. Provisional Application No.60/777,939, filed on Feb. 28, 2006, herein incorporated by reference inits entirety.

This invention was made in part through funds from the Department ofVeterans Affairs. As such, the United States government has certainrights in the invention.

FIELD OF THE INVENTION

The present invention relates to the co-administration of twoneurotransmitter agonists to patients with motor disorders, for thepurpose of symptom reduction. In particular the present inventionprovides methods and compositions for alleviation of akinesia, rigidityand/or tremor associated with Parkinson's disease.

BACKGROUND OF THE INVENTION

Parkinson's disease is a chronic, progressive, hypokinetic disordercharacterized by impaired voluntary movement (See, Dale and Federman(eds.), WebMD Scientific American Medicine, NY: WebMD Corporation,Chapter 11, Section 15, pp. 1-21, 2001; Lang and Lozano, N Engl J Med,339:1044, 1998; and Lang and Lozano, N Engl J Med, 339:1130, 1998).Parkinson's disease occurs as a result of the death ofdopamine-producing neurons in the substantia nigra of the midbrain.Dopamine is a neurotransmitter, or chemical messenger, that transportssignals to the parts of the brain that control movement initiation andcoordination. The loss of dopamine in the brain is associated withmultiple primary symptoms including: tremor of the hands, arms, legs,jaw, and face; rigidity or stiffness of the limbs and trunk;bradykinesia or slowness of movement; and postural instability orimpaired balance and coordination.

Parkinson's disease afflicts more than one million persons in the UnitedStates alone (Lang and Lozano, supra, 1998), with approximately 50,000new cases diagnosed each year. It is generally a disease of late middleage, with typical onset occurring at about age 60. About five percent ofpatients, however, have early-onset disease and are younger than 40 whensymptoms begin.

Most current treatment strategies for Parkinson's disease (PD) focus onsymptom control through one or more of medication, surgery, and physicaltherapy. The dopamine precursor, levodopa (L-DOPA) is still consideredto be the gold standard in terms of treatment for PD (Schapira andOlanow, JAMA, 291:358-364, 2004). Unfortunately, L-DOPA can causedebilitating side effects (LeWitt and Nyholm Neurology, 62:S9-S16,2004), including severe nausea, vomiting, and psychosis. Moreover, withprolonged use, patients frequently experience other side effects such asdyskinesias (spontaneous, involuntary movements) and “on-off” periodswhen the medication will suddenly start or stop working.

Surgical treatments are considered for patients with advanced disease orwho have not responded adequately to medications. Accepted surgicaltreatments involve either the creation of small, precise lesions or theimplantation of stimulating electrodes in specific brain regions thatappear to be overactive in Parkinson's disease. More recently,implantation of fetal dopaminergic tissue has been utilized as a meansof restoring dopamine levels in the brains of patients with Parkinson'sdisease (See, e.g., Freed et al., Arch Neurol, 47:505-512, 1990; andLindvall et al., Science, 247:574-577, 1990). These types of methods,however, are highly invasive.

Thus, what is needed in the art are noninvasive treatment strategies foreffectively controlling symptoms of Parkinson's disease and othermovement disorders. In addition, it would be desirable to be inpossession of therapy regimens that maximize the efficacy of existingmedicines.

SUMMARY OF THE INVENTION

The present invention relates to the co-administration of twoneurotransmitter agonists to patients with motor disorders, for thepurpose of symptom reduction. In particular the present inventionprovides methods and compositions for alleviation of akinesia, rigidityand/or tremor associated with Parkinson's disease, as well as foralleviation of side effects associated with treatment associated withParkinson's disease.

The present invention provides methods of treating a motor disorder,comprising: providing: i) a serotonin type 1A (5-HT1A) receptor agonist,ii) a dopamine receptor agonist, and iii) a subject diagnosed as havinga motor disorder; and b) administering the serotonin type 1A receptor(5-HT1A) agonist to the subject during a pre-conditioning period; and c)co-administering the serotonin type 1A receptor (5-HT1A) agonist incombination with a low dose of the dopamine receptor agonist to thesubject, under conditions suitable for reducing at least one symptom ofthe motor disorder, wherein the low dose of the dopamine receptoragonist is below that required for reducing at least one symptom of themotor disorder when administered in the absence of the serotonin type 1A(5-HT1A) receptor agonist. In some embodiments, the motor disorder isParkinson's disease. In other embodiments, the motor disorder isparkinsonism arising from viral infection or drug use. In some preferredembodiments, the dopamine receptor agonist is not a dopamine precursor.In some embodiments, the serotonin type 1A (5-HT1A) receptor agonist isselected from the group consisting of arylpiperazines, azapirones,aminotetralins, and aminochromanes. In other embodiments, the serotonintype 1A (5-HT1A) receptor agonist is8-hydroxy-2-(di-n-propylamino)tetralin (80H-DPAT). In some preferredembodiments, 80H-DPAT is administered via a transdermal patch. In someembodiments, the serotonin type 1A (5-HT1A) receptor agonist is selectedfrom the group consisting of tandospirone, ipsapirone, gepirone,flibanserin, flesinoxan, sarizotan, repinotan and PRX-00023. In somepreferred embodiments, the dopamine receptor agonist is a D1 typedopamine receptor agonist. In a subset of these embodiments, the D1 typedopamine receptor agonist is selected from the group consisting ofSKF38393, SKF83959, SKF81297, SKF77434, SKF75670, SKF82958, andderivatives thereof. In further embodiments, the D1 type dopaminereceptor agonist is selected from the group consisting of dihydrexidine,dinapsoline, A-77636, ABT-431, CY208-243, and A-68930. In otherembodiments, the dopamine receptor agonist is a D2 type dopaminereceptor agonist. In some of these embodiments, the D2 type dopaminereceptor agonist is quinpirole. In other embodiments, the D2 typedopamine receptor agonist is selected from the group consisting ofquinelorane, terguride, pergolide, talipexole, pramipexole, sumanirole,ropinirole, roxindole, bromocriptine, and cabergoline. In still furtherembodiments, the dopamine agonist is a dopamine precursor. In a subsetof these embodiments, the dopamine precursor is levodopa (L-DOPA), whichis administered with one or both of a L-aromatic amino aciddecarboxylase inhibitor (e.g., carbidopa, benserazide,difluromethyldopa, a-methyldopa, etc.) and acatechol-O-methyltransferase (COMT) inhibitor (e.g., tolcapone andentacapone). In still further embodiments one or both of the serotonintype 1A (5-HT1A) receptor agonist and the dopamine receptor agonist is aD1 type dopamine receptor agonist. In a subset of these embodiments, theserotonin type 1A (5-HT1A) receptor agonist is selected from the groupconsisting of sunipetron and aripiprazole. Also provided are methodsfurther comprising administering a low dose of the dopamine receptoragonist to the subject during the pre-conditioning period, wherein thelow dose is of the dopamine receptor agonist is below that required forreducing at least one symptom of the motor disorder when administered inthe absence of the serotonin type 1A (5-HT1A) receptor agonist.

In some preferred embodiments, the present invention provides methods oftreating Parkinson's disease, comprising: providing: i) a serotonin type1A (5-HT1A) receptor agonist, ii) a dopamine receptor agonist, and iii)a subject diagnosed as having Parkinson's disease; and b) administeringthe serotonin type 1A receptor (5-HT1A) agonist to the subject during apre-conditioning period; and c) co-administering the serotonin type 1Areceptor (5-HT1A) agonist in combination with a low dose of the dopaminereceptor agonist to the subject, under conditions suitable for reducingat least one symptom of Parkinson's disease, wherein the low dose of thedopamine receptor agonist is below that required for reducing at leastone symptom of Parkinson's disease when administered in the absence ofthe serotonin type 1A (5-HT1A) receptor agonist. In some particularlypreferred embodiments, the at least one symptom comprises one or more ofbradykinesia, tremor, and muscle rigidity. Also provided are embodimentsin which the co-administering the serotonin type 1A receptor (5-HT1A)agonist in combination with the dopamine receptor agonist to the subjectis under conditions further suitable for reducing at least one sideeffect of the dopamine receptor agonist. In some preferred embodiments,the at least one side effect of the dopamine receptor agonist comprisesdyskinesia (e.g., one or more of chewing, gnawing, twisting, tongue ormouth movements, head bobbing, and movements of the feet, hands, orshoulder). In other embodiments, the at least one side effect of thedopamine receptor agonist comprises a psychiatric disturbance (e.g., oneor more of memory loss, anxiety, nervousness, agitation, restlessness,confusion, inability to sleep, nightmares, daytime tiredness, mentaldepression and euphoria). In some preferred embodiments, the dopaminereceptor agonist is not a dopamine precursor.

Moreover, the present invention provides methods for treating a subject,comprising: providing; i) a serotonin type 1A (5-HT1A) receptor agonist,ii) a dopamine receptor agonist, iii) a subject receiving the dopaminereceptor agonist for treatment of Parkinson's disease, wherein thesubject is suffering from dopamine receptor agonist-induced dyskinesia;co-administering the serotonin type 1A receptor (5-HT1A) agonist incombination with the dopamine receptor agonist to the subject during apreconditioning period under conditions suitable for reducing thedopamine receptor agonist-induced dyskinesia; co-administering theserotonin type 1A receptor (5-HT1A) agonist in combination with thedopamine receptor agonist to the subject during a dosage optimizationperiod, wherein dosage of the dopamine receptor agonist is graduallyreduced until at least one symptom of the Parkinson's disease isre-emerges; and co-administering the serotonin type 1A receptor (5-HT1A)agonist in combination with the dopamine receptor agonist to the subjectunder conditions suitable for reducing the at least one symptom of theParkinson's disease, while reducing the dopamine receptoragonist-induced dyskinesia, wherein dosage of the dopamine receptoragonist is below that of step b and above that of step c.

In addition, the present invention provides kits for treatingParkinson's disease comprising a serotonin type 1A (5-HT1A) receptoragonist, a dopamine receptor agonist, and instructions for administeringthe serotonin type 1A (5-HT1A) receptor agonist and the dopaminereceptor agonist to a subject diagnosed as having Parkinson's disease,wherein the dopamine receptor agonist is administered at a dose belowthat required for reducing at least one symptom of the Parkinson'sdisease when administered in the absence of the serotonin type 1A(5-HT1A) receptor agonist. In some embodiments, the kit comprises apackage (e.g., blister pack). In some preferred embodiments, thedopamine receptor agonist is not a dopamine precursor.

Also provided are compositions for treating Parkinson's diseasecomprising: a therapeutic dose of a serotonin type 1A (5-HT1A) receptoragonist and a subtherapeutic dose of a dopamine receptor agonist. Insome preferred embodiments, the dopamine receptor agonist is not adopamine precursor. In some particularly preferred embodiments, thecompositions further comprise a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the effects of repeated daily dosing with L-DOPA (10mg/kg+6.25 mg/kg benserazide) or L-DOPA plus R(+)-8-OHDPAT (0.3 mg/kg).Ipsilateral turning as well as contralateral turning was recorded andquantified.

FIG. 2 demonstrates that a 5-HT_(1A) agonist enhances theanti-parkinsonian action of a D₁ type dopamine agonist as demonstratedby contralateral turning in the unilateral 6-OHDA-lesioned rat. The5-HT_(1A) agonist R(+)-8-OHDPAT (0.3 mg/kg) or vehicle (0.9% salinecontaining ascorbate) was administered for 14 days. On Day 15, rats weregiven either vehicle or R(+)-8-OHDPAT (0.3 mg/kg), plus a low dose D₁agonist SKF 38393 (0.1 mg/kg) and observed for 3 hr.

FIG. 3 demonstrates that a 5-HT_(1A) agonist enhances theanti-parkinsonian action of a D₂ type dopamine agonist as demonstratedby contralateral turning in the unilateral 6-OHDA-lesioned rat. The5-HT_(1A) agonist R(+)-8-OHDPAT (0.3 mg/kg) or vehicle (0.9% salinecontaining ascorbate) was administered for 14 days. On Day 15, rats weregiven either vehicle or R(+)-8-OHDPAT (0.3 mg/kg), plus a low dose D₂agonist quinpirole (0.05 mg/kg) and observed for 3 hr.

FIG. 4 illustrates that both repeated and concomitant administration ofa serotonin agonist was required to enhance that anti-parkinsonianactions of a dopamine agonist.

FIG. 5 demonstrates that repeated administration of R(+)-8-OHDPATreduced dyskinetic behavior elicited by a moderately high dose of the D₁agonist SKF 38393 (3.0 mg/kg).

FIG. 6 demonstrates that repeated administration of R(+)-8-OHDPATreduced dyskinetic behavior elicited by a moderately high dose of the D₂agonist quinpirole (0.05 mg/kg).

FIG. 7 illustrates that pre-treatment with a selective 5-HT1A antagonist(WAY 100635) blocked the facilitating effects of a serotonin agonist onthe anti-parkinsonian action of a dopamine agonist.

FIG. 8 is an image of an immunoblot of striatal extracts probed with ananti-Fos antibody.

FIG. 9 illustrates that once daily administration of L-DOPA (25 mg/kgplus 6.25 mg/kg benserazide) or SKF 38393 (1 mg/kg) for 15 days elicitsa significant increase in ΔFosB in the denervated striatum of unilateral6-OHDA-lesioned rats (*, significantly greater than vehicle-treated;p<0.05). The concomitant administration of the 5-HT1 A agonistR(+)-8-OHDPAT (0.3 mg/kg) with SKF 38393 prevents the D1 agonist-inducedrise in ΔFosB (#, significantly less than VEH+SKF; p<0.05 and notsignificantly different from vehicle-treated).

FIG. 10 depicts the rotational response in rats given once dailyadministration of vehicle+SKF 38393 (0.1, 0.3 or 1.0 mg/kg) for 15 days.Animals receiving once daily R(+)-8-OHDPAT (0.3 mg/kg) plus SKF 38393displayed a significantly greater contralateral turning response thatdisplayed a dose-dependency with respect to the dose of SKFadministered.

FIG. 11 compares the rotational response between pre-screened (“primed”)and non-pre-screened (“unprimed”) rats after 15 days of once dailyadministration of R(+)-8-OHDPAT (0.3 mg/kg) plus SKF 38393 (0.3 mg/kg).There is no significant difference between the groups.

DEFINITIONS

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below:

The terms “Parkinson's disease,” “Parkinson's” and “PD” refer to aneurological syndrome characterized by a dopamine deficiency, resultingfrom degenerative, vascular, or inflammatory changes in the basalganglia of the substantia nigra. This term also refers to a syndromewhich resembles Parkinson's disease, but which may or may not be causedby Parkinson's disease, such as Parkinsonian-like side effects caused bycertain antipsychotic drugs. Parkinson's disease is also referred to asparalysis agitans and shaking palsy.

As used herein, the term “early stage of Parkinson's disease” refersbroadly to the first stages in Parkinson's disease, wherein a personsuffering from the disease exhibits mild symptoms that are notdisabling, such as an episodic tremor of a single limb (e.g., the hand),and which affect only one side of the body.

In contrast, the term “advanced stage of Parkinson's disease” refersbroadly to a more progressive stage in Parkinson's disease, wherein aperson suffering from the disease exhibits symptoms which are typicallysevere and which may lead to some disability (e.g., tremors encompassingboth sides of the body, balance problems, etc.). Symptoms associatedwith advanced stage Parkinson's disease may vary significantly inindividuals, and may take many years to manifest after the initialappearance of the disease.

The terms “subject suffering from a Parkinson's disease” and “subjectsuffering from parkinsonism” as used herein, refer to both humans andanimals displaying one or more symptom of Parkinson's disease. Theprimary symptoms of Parkinson's disease include bradykinesia, tremor,and muscle rigidity. The term “animals” refers to all non-human animals.Such non-human animals include, but are not limited to, vertebrates suchas rodents, non-human primates, ovines, bovines, lagomorphs, porcines,caprines, equines, canines, felines, ayes, etc.

The terms “dopamine,” “DA” and “4-(2-aminoethyl)benzene-1,2-diol,” referto a catecholamine neurotransmitter and hormone, formed first by thehydroxylation of the amino acid tyrosine to dihydroxyphenylalanine(dopa), and then by decarboxylation of dihydroxyphenylalanine (dopa) todopamine. Dopamine is a precursor of adrenaline (epinephrine) andnoradrenaline (norepinephrine).

The terms “serotonin,” “5-hydroxytryptamine” and “5-HT” refers to aphenolic amine neurotransmitter produced from tryptophan byhydroxylation and decarboxylation in serotonergic neurons of the centralnervous system and enterochromaffin cells of the gastrointestinal tract.Serotonin is a precursor of melatonin.

As used herein, the term “symptoms” refers to the outward manifestationsof a disease. For instance, patients with Parkinson's disease exhibitsymptoms such as bradykinesia, tremor, and muscle rigidity. Additionalsymptoms but are not limited to atypical gait, postural instability, andloss of balance.

The term “alleviating” refers to the act of providing relief from somepainful state. As used herein, the term “alleviating” refers to thelessoning of symptoms of Parkinson's disease or to the lessoning of sideeffects associated with long term L-dopa administration. In someembodiments, the term “alleviating” comprises curing Parkinson'sdisease. In other embodiments, the term “alleviating: comprisesdecreasing the severity of the symptoms of Parkinson's disease asmeasured by any one of several accepted diagnostic measures includingbut not limited to UPDRS, Schwab and England Scale, and CAPIT.

The terms “Unified Parkinson's Disease Rating Scale” and “UPDRS” referto a standardized tool used to measure Parkinson's Disease severity, asdescribed by Fahn et al., in Recent Developments in Parkinson's Disease,Fahn et al. (eds.) Plurham Park, N.J.: Macmillian HealthcareInformation, 2:153-163, 1987.

“The term “Schwab and England Scale” refers to a standardized tool usedto measure the efficacy of surgical treatment for Parkinson's Disease,as described by Schwab and England, in Third Symposium on Parkinson'sDisease, Gillingham and Donaldon (eds.) Edinburgh, Scotland:Livingstone, pp. 152-157, 1969.

The terms “Core Assessment Program for Intracerebral Transplantation”and “CAPIT” refer to a standardized tool used to measure the efficacy ofcerebral surgery, as described by Langston et al., Mov Disord, 7:2-13,1992.

The terms “agonist” and “stimulator” refers to molecules or compoundsthat mimic the action of a “native” or “natural” compound. Agonists maybe homologous to these natural compounds in respect to conformation,charge or other characteristics. Thus, agonists may be recognized byreceptors expressed on cell surfaces. This recognition may result inphysiologic and/or biochemical changes within the cell, such that thecell reacts to the presence of the agonist in the same manner as if thenatural compound was present. The term “agonist” also encompasses theclass of agents known as partial agonists, in which the maximalphysiologic and/or biochemical changes that occur upon partial agonistadministration may be less than the maximal effect exhibited by fullagonists or the natural compound. In preferred embodiments, the termagonist refers to molecules that bind to and activate one or both ofserotonin type 1A and dopamine type receptors.

As used herein, the terms “antagonist” and “inhibitor” refer tomolecules or compounds that inhibit the action of a “native” or“natural” compound. Antagonists may or may not be homologous to thesenatural compounds in respect to conformation, charge or othercharacteristics. Thus, antagonists may be recognized by the same ordifferent receptors than are recognized by an agonist. Antagonists mayhave allosteric effects, which prevent the action of an agonist. Incontrast to the agonists, antagonistic compounds do not result inphysiologic and/or biochemical changes within the cell, such that thecell reacts to the presence of the antagonist in the same manner as ifthe natural compound was absent.

As used herein the term “subtherapeutic dose” refers to a quantity of aneurotransmitter agonist (e.g., D1 agonist) below that used to treatdisease when used as a monotherapy. In an exemplary embodiment, asubtherapeutic dose of a D1 agonist is equivalent to 5 mg of SKF38393administered to an adult human subject four times a day.

As used herein, the term “therapeutic dose” refers to a quantity of aneurotransmitter agonist (e.g., 5-HT1A agonist) used to treat disease(e.g., effect the cure of or that will correct the manifestations of adisease). In an exemplary embodiment, a therapeutic dose of a 5-HT1Aagonist is equivalent to 5 mg of sarizotan administered to an adulthuman subject two or three times per day. In another exemplaryembodiment, a therapeutic dose of a 5-HT1A agonist is equivalent to 5 mgof ipsapirone administered to an adult human subject four times a day.

DESCRIPTION OF THE INVENTION

The present invention relates to the co-administration of twoneurotransmitter agonists to patients with motor disorders, for thepurpose of symptom reduction. In particular the present inventionprovides methods and compositions for alleviation of akinesia, rigidityand/or tremor associated with Parkinson's disease.

Neurotransmitters

Parkinson's disease (PD) and related neurological disorders (e.g.postencephalitis parkinsonism, Hallervorden-Soatz disease) involve theprogressive degeneration of dopamine neurons innervating the striatum.The loss of dopamine leads to excessive inhibition of thalamocorticalmotor activity, for which the primary manifestations are rigidity,bradykinesia, tremor and postural instability (Fahn, Ann NY Acad Sci,991:1-14, 2003; and Hamani and Lozano, Ann NY Acad Sci, 991:15-21,2003). The striatum is a major input structure that receives densedopaminergic projections from the substantia nigra pars compacta andglutamatergic projections from the cortex and thalamus. Two efferentpathways originate in the striatum and utilize the inhibitorytransmitter gamma-aminobutyric acid (GABA). The direct pathway iscomprised of medium spiny striatonigral neurons that project directly tothe output nuclei of the basal ganglia, which are the internal globuspallidus (rat homologue is the entopeduncular nucleus or EP) and thesubstantia nigra pars reticulata (SNr). These striatonigral neuronspredominantly express dopamine D₁ receptors and co-express dynorphin andsubstance P (Gerfen, Clin Neuropharmacol, 18:S162-S177, 1995). Theindirect pathway is comprised of medium spiny striatopallidal neuronsthat project to the external globus pallidus (GP). These striatopallidalneurons predominantly express dopamine D₂ receptors and co-expressenkephalin (Gerfen, supra, 1995). The GP sends GABA projections to thesubthalamic nucleus (STN), which in turn, sends glutamate projections tothe EP and SNr. The EP and SNr serve as the final output structures ofthe basal ganglia and innervate the motor thalamus with inhibitory GABAprojections. In PD and pre-clinical models of PD there is evidence ofde-synchronization and hyperactivity in the STN, EP and SNr (Breysse etal., J Neurosci, 23:8302-8309, 2003; and Wichmann and DeLong, Ann NYAcad Sci, 991:199-213, 2003). Overactivity or dysregulated activity ofthese nuclei contributes to the motor deficits of PD.

Dopamine Replacement Therapy

The effects of D₁ agonists on striatonigral activity are somewhatcontroversial (Calabresi et al., Neurosci Biobehav Rev, 21:519-523,1997). However, in the dopamine-denervated rat, D₁ agonists enhance therelease of GABA within the SNr, as measured by in vivo microdialysis(You et al., Neurosciece, 63:427-434, 1994; and Trevitt et al.,Psychopharmacol, 159:229-237, 2002). Increased GABA would be expected toreduce SNr inhibition to the thalamus and increase motor activity.Stimulation of D₂ receptors in the dopamine-denervated rat inhibitsstriatopallidal activity as a result of reducing glutamatergic activityfrom the cortex (Centonze et al., Clin Neurophysiol, 110:2006-2013,1999). A downstream consequence of this action is a reduction inglutamate release from the STN projections in the output nuclei, whichcan be measured by in vivo microdialysis in the SNr or EP (Biggs et al.,Brain Res, 753:163-175, 1997; and Biggs and Starr, Neurosci BiobehavRev, 21:497-504, 1997). These techniques are contemplated to be usefulfor monitoring the effects on excitatory and inhibitory transmissions inthe output nuclei of the anti-parkinsonian therapies of the presentinvention.

In the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD,6-OHDA is used to selectively lesion dopamine neurons innervating thestriatum on one side, thereby causing greater thalamic inhibition on thelesioned side (Schwarting and Huston, Prog Neurobiol, 50:275-331, 1996;and Deumens et al., Exp Neurol, 175:303-317, 2002). Agents that modifybasal ganglia output manifest their effects as rotational behavior, thequantity and duration of which can be readily quantified. This model hasalso been used to assess the dyskinetic potential of drug treatments.Along these lines, a progressive increase in rotational response isobserved upon repeated daily treatment with DA agonists or L-DOPA. Thisaugmentation of behavior is often referred to as “priming” and has beentaken as an index of dyskinetic potential, although there is currentlyconsiderable debate as to whether “priming” is exclusively indicative ofmotor complications (Di Chiara et al., Dev Pharmacol Ther, 18:223-227,1992; and Henry et al., Exp Neurol, 151:334-342. 1998; Lane et al., ExpNeurol, 197:284-290, 2006; Marin et al., Exp Neurol, 197:269-274, 2006).Numerous studies have used this phenomenon to establish associationsbetween the priming effect and neurobiological changes.

Selective D₁ agonists and selective D₂ agonists have demonstratedefficacy in rodent and primate models of PD (Schwarting and Huston,supra 1996; and Rascol et al., Ann Neurol, 45:736-741, 1999). However,only L-DOPA and D₂ agonists have found widespread use in treating PD(Jenner, Curr Opin Neurol, 16(S1):S3-S7, 2003). D₂ agonists have beenutilized as monotherapy for mild or early stage PD and as adjuncts toL-DOPA in more advanced PD. If therapy is initiated with D₂ agonistsalone, the incidence of dyskinesia is drastically reduced (Jenner, supra2003). Unfortunately, D₂ agonists do not display the spectrum ofefficacy seen with L-DOPA and as PD progresses L-DOPA therapy isfrequently initiated (Jenner, supra 2003; and Lang and Lees, Mov Disord,17(S4):S23-S37, 2002). Motor fluctuations and dyskinesias emerge astreatment with L-DOPA continues. It has been suggested that D₁ agonistsmay show a more favorable therapeutic profile than existing medications,but there has been little success with D₁ agonists for PD in the past(Emre et al., Mod Disord, 7:239-243, 1992; and Rascol et al., supra,1999). There is a clear need to improve on drug therapy for PD.

The preferred dopamine receptor agonists for use with the presentinvention are partial agonists of the D1 dopamine receptor subtypes.Particular examples of such compounds are benzazepine derivatives suchas SKF38393, SKF83959, SKF81297, SKF77434, SKF75670, SKF82958(Pettersson et al., J Med Chem, 33:2197-2204, 1990; and Neumeyer et al.,Eur J Pharmacol, 474:137-140, 2003). In some particularly preferredembodiments when given alone their anti-Parkinsonian action would beminimal or not evident. In further embodiments, full agonists of the D1receptor are used. Examples of such compounds are tetrahydroisoquinolinederivatives such as dinapsoline (Ghosh et al., J Med Chem, 39:549-555,1996), conformationally restricted phenanthridines such as dihydrexidine(Brewster et al., J Med Chem, 33:1756-1764, 1990), isochromans such asA68930, tetrahydroisoquinoline derivatives such as dinapsoline (Ghosh etal., J Med Chem, 39:549-555, 1996) and benzopyrans such as A-68930 andA-77636 (DeNinno et al., J Med Chem 33:2948-2950, 1990). However, inpreferred embodiments full agonists of the D1 receptor are used at asignificantly reduced dosage (e.g., at or below the threshold ofclinical efficacy) as compared to the dosage used as monotherapy. Infurther embodiments, partial agonists of the D2 receptor subtype or fullagonists of the D2 receptors are used (Jenner Curr Opin Neurol 16[Suppl1]:S3-S7, 2003; Bonucelli Curr Opin Neurol 16[Suppl 1]:S13-S19, 2003),as described for D1 agonists.

Serotonin Adjuvant Therapy

The preferred serotonin (5-HT) receptor agonists for use with thisinvention are full agonists at the 5-HT1A receptor subtype, or partialagonists with moderate to high efficacy at the 5-HT1A receptor subtype.Particular examples of such compounds include phenylpiperazines such asflesinoxan, eltoprazine, ipsapirone, gepirone, tandospirone, buspirone,eltoprazine, befiperide, BMY7378, flibanserin, and aripiprazole (See,e.g., van Steen et al., J Med Chem, 36:2751-2760, 1993; van Steen etal., J Med Chem, 37:2761-2773, 1994; van Steen et al., J Med Chem,38:4303-4308, 1995; Kuipers et al., J Med Chem, 38:1942-1954, 1995;Kuipers et al., J Med Chem, 40:300-312, 1997; and Heinrich et al., J MedChem, 47:4684-4692, 2004). Particular examples also include substitutedchromane derivatives such as sarizotan, 8-OHDPAT, alnespirone, BAY X3702 (De Vry et al., J Pharmacol Exp Ther, 284:1082-1094, 1998; andHammarberg et al., J Med Chem, 43:2837-2850, 2000) andpyridinemethylamine derivatives (Vacher et al., J Med Chem,42:1648-1660, 1999).

Serotonin Preconditioning Period

The preconditioning period refers to the length of time required forpretreatment with a 5-HT1A receptor agonist (in the presence or absenceof a dopamine agonist) before an anti-Parkinsonian effect is observed inresponse to combined 5-HT1A agonist-dopamine agonist therapy. Thisperiod is hypothesized to reflect the time required for neural changesto occur in response to the repeated 5-HT1A agonist administrations.Nonetheless, an understanding of the mechanism is not necessary in orderto make and use the present invention. It is contemplated that a simpleassessment of levels of the 5-HT metabolite 5-hydroxyindoleacetic acid(5-HIAA) in blood taken at the onset of 5-HT1A agonist treatment andfollowing repeated 5-HT1A agonist administration (e.g., days to weeks)provides an indication as to whether the preconditioning period isadequate. For instance, a 20% or greater difference in 5-HIAA levelbetween first and second sampling in which the 5-HIAA is lower at firstsampling and the 5-HIAA level from the second sampling is anticipated tobe in the range of 4.2-18.9 ng/ml (Yeung et al., J Pharm Sci, 85:451-453, 1996) is contemplated to be indicative of sufficientpreconditioning. Alternatively, a comparison of the plasma levels ofcortisol and change in body temperature in response to the firstadministration of drug versus responses following drug administrationafter several weeks of treatment is also contemplated to be useful forassessing whether the preconditioning period is sufficient for effectingan anti-Parkinsonian response to subsequent combined 5-HT1Aagonist-dopamine agonist therapy. For instance, an increase in plasmacortisol of 30% or greater and a reduction in body temperature of 0.2°C. or greater when assessed 90 minutes after drug intake is expectedfollowing initial 5-HT1A agonist treatment (Sargent et al.,Psychopharmacol, 132: 296-302, 1997; and Yatham et al., J Affect Dis,54:295-301, 1999). It is contemplated that a significant attenuation ofthese responses will be seen when assessed 90 minutes following drugintake in patients that have received a sufficient preconditioningperiod of treatment (Sargent et al., Psychopharmacol, 132: 296-302,1997).

EXPERIMENTAL

The following examples are provided in order to demonstrate and furtherillustrate certain preferred embodiments and aspects of the presentinvention and are not to be construed as limiting the scope thereof.

In the experimental disclosure which follows, the followingabbreviations apply: U (units); N (normal); M (molar); mM (millimolar);μM (micromolar); mol (moles); mmol (millimoles); μmol (micromoles); nmol(nanomoles); pmol (picomoles); g (grams); mg (milligrams); μg(micrograms); ng (nanograms); 1 or L (liters); ml (milliliters); μl(microliters); cm (centimeters); mm (millimeters); μm (micrometers); nm(nanometers); ° C. (degrees Centigrade); OD (optical density); by (basepairs); PCR (polymerase chain reaction); RT (reverse transcriptase);DMEM (Dulbecco's modified Eagle medium); EDTA(ethylenediaminetetraacetic acid); FBS (fetal bovine serum); L-DOPA(levodopa); 6-OHDA (6-hydroxydopamine); and PBS (phosphate bufferedsaline).

Example 1 Motor Effects of Co-Administration of a Serotonin Agonist andL-DOPA in a Rat Model of Parkinson's Disease

Preparation of hemi-lesioned 6-hydroxydopamine (6-OHDA)-treated ratmodel of Parkinson's disease.

Rats were rendered parkinsonian on one side of the brain by unilateraldestruction of nigrostriatal dopamine neurons using the selectiveneurotoxin 6-OHDA and stereotaxic procedures. Animals were allowed torecover for at least 2 weeks following this procedure. Animals were thenscreened for efficacy of the lesion by subcutaneous injection of L-DOPA(25 mg/kg) plus the decarboxylase inhibitor benserazide (6.25 mg/kg)followed by assessment of motor activity.

Assessment of Motor Activity.

Anti-parkinsonian action in the hemi-lesioned 6-OHDA-treated rat modelwas assessed by the elicitation of rotational activity to the sideopposite the lesioned hemisphere (contralateral turns) following drugtreatment. The number of contralateral turns was assessed by videotaperecording of animals and counting the number of turns.

Assessment of Dyskinetic Activity.

Observer assessment of motor dyskinesias was carried out be viewing thevideotaped recording of rats during testing for rotational activity. Adyskinesia score was generated at 10 minute intervals throughout thecourse of the rotational test (generally 3 hr). Dyskinesia scores werebased on the following scale: 0—no evidence of abnormal activity;1—mild, intermittent forelimb dyskinesia; 2—severe, more persistentforelimb dyskinesia associated with animal directing activity towardforelimb; 3—severe limb and axial dyskinesia associated with loss ofbalance and consistent “barrel-rolling” activity. The dyskinesia scoresthat were obtained were averaged to generate a dyskinesia index.

Treatment and Results.

Rats that demonstrated contralateral turning indicative of a successfullesion received a daily subcutaneous injection of L-DOPA (10 mg/kg+6.25mg/kg benserazide) or L-DOPA plus R(+)-8-OHDPAT (0.3 mg/kg). Ipsilateralturning as well as contralateral turning was recorded and quantified. Asshown in FIG. 1, L-DOPA elicited almost exclusively contralateralturning, which became progressively greater upon repeated daily dosing.This represents the “priming” phenomenon, which may reflectneurobiological changes associated with L-DOPA-induced dyskinesias aswell as an anti-Parkinsonian response (Lane et al., Exp Neurol197:284-290, 2006). Although not quantified in this experiment, theturning response of L-DOPA-treated animals was observed to becomeprogressively more uncoordinated upon repeated L-DOPA administration,suggesting the emergence of dyskinetic activity. Despite this,L-DOPA-treated animals turned approximately 3-fold more on Day 15 thanon Day 1. Animals treated with L-DOPA plus R(+)-8-OHDPAT displayedipsilateral turning early in the observation period (first 30 min) andthen exhibited contralateral turning. The ipsilateral turning could beelicited by R(+)-8-OHDPAT treatment alone. Even so, contralateralturning elicited by L-DOPA plus R(+)-8-OHDPAT on Day 15 wasapproximately 2-fold greater than the contralateral turning exhibited onDay 1. Given that augmented turning can be used as an index ofdyskinesia, the inventors cannot discount the possibility that ratsreceiving the combined treatment had displayed evidence of dyskineticpotential. However the inventors also noted that rats receiving thecombined treatment turned in a much more natural, coordinated fashion.These observations are in line with a published report of reduced motorcomplications of levodopa treatment upon coadministration of the5-HT_(1A) agonist sarizotan (Bibbiani et al., Neurology, 57:1829-1834,2001).

Example 2 A Serotonin Agonist Enhances the Anti-Parkinsonian Actions ofDopamine Agonists in a Rat Model of Parkinson's Disease

Treatment.

Hemi-lesioned 6-OHDA-treated rat that demonstrated contralateral turningindicative of a successful lesion were split into 2 groups that werebalanced with respect to motor response to L-DOPA during screening. Onegroup (controls) received a daily subcutaneous injection of vehicle(0.9% saline containing 0.1 mg/kg ascorbate; 1 ml/kg) for 14 days andthe other group (8-OHDPAT) received a daily subcutaneous injection ofR(+)-8-OHDPAT (0.3 mg/kg in 1 ml/kg volume) for 14 days. Beginning onday 15, both groups of rats were tested for motor activity anddyskinetic activity in response to the D1 receptor partial agonist SKF38393 or the D2 receptor agonist quinpirole. Such testing was carriedout in a randomized fashion with different doses of dopamine agonistbeing tested every 4^(th) day (e.g. 3 days between dopamine agonistadministration). Throughout this testing phase the control groupcontinued to receive daily injection of vehicle and the 8-OHDPAT groupcontinued to receive daily injection of 0.3 mg/kg R(+)-8-OHDPAT. On dayswhen dopamine agonists were tested the vehicle or R(+)-8-OHDPAT wasadministered simultaneously with the dopamine agonist.

Results.

FIGS. 2 and 3 illustrate that administration of a 5-HT1A agonistenhances the anti-parkinsonian action of D1 and D2 agonists, asdetermined by quantitating contralateral turning in the hemi-lesioned6-OHDA-treated rat. In both experiments animals were given the 5-HT1Aagonist R(+)-8-OHDPAT (0.3 mg/kg) or vehicle (0.9% saline containingascorbate) for 14 days. Rats that received R(+)-8-OHDPAT for 14 dayswere then given R(+)-8-OHDPAT (0.3 mg/kg) plus a dopamine agonist ontest day, and were observed for 3 hr for anti-parkinsonian effect(contralateral turning). Rats that received vehicle for 14 days werethen given a vehicle plus the dopamine agonist on test day, and wereobserved for 3 hr for anti-parkinsonian effect (contralateral turning).FIG. 2 depicts the data obtained when the D1 agonist SKF 38393 (0.1mg/kg) was administered on test day. Animals that received R(+)-8-OHDPATexhibited pronounced contralateral turning when SKF 38393 wasadministered. This turning behavior was significantly greater than whatwas observed for animals that received vehicle (p<0.005). In fact,animals that received vehicle plus SKF 38393 displayed no contralateralturning. FIG. 3 depicts the data obtained when the D2 agonist quinpirole(0.05 mg/kg) was administered on test day. Animals that receivedR(+)-8-OHDPAT exhibited significantly greater contralateral turningfollowing quinpirole as compared to animals that received vehicle plusquinpirole (p<0.001).

Example 3 The Anti-Parkinsonian Effect of a Serotonin Agonist RequiresRepeated Administration

Repeated Administration of a 5-HT1A Agonist.

The methods described in the previous examples were used to examine theeffects of acute and chronic administration of the 5-HT1A agonist,R(+)-8-OHDPAT. The dose of both R(+)-8-OHDPAT and SKF 38393 was 0.3mg/kg throughout this experiment. FIG. 4 graphically depicts the resultsof an experiment in which animals received either a) 14 days ofR(+)-8-OHDPAT followed by SKF 38393 plus vehicle on test day, b) 14 daysof R(+)-8-OHDPAT followed by SKF 38393 plus R(+)-8-OHDPAT on test day,c) 14 days of vehicle followed by SKF 38393 plus vehicle on test day, ord) 14 days of vehicle followed by SKF 38393 plus R(+)-8-OHDPAT on testday. Animals that received 14 day pretreatment with R(+)-8-OHDPAT plusconcomitant R(+)-8-OHDPAT+SKF 38393 on test day exhibited significantanti-parkinsonian action greater than all other treatment groups(p<0.001). These data indicate that brain adaptations arising as aresult of chronic treatment with R(+)-8-OHDPAT are necessary, but notsufficient, to enhance the anti-parkinsonian actions of dopamineagonists. These data also indicate that concomitant administration of a5-HT1A agonist plus a dopamine agonist is necessary, but not sufficient,to enhance the anti-parkinsonian actions of dopamine agonists. Thus asdetermined during development of the present invention, both chronic andconcomitant administration of a 5-HT1A agonist are required to achieveenhanced anti-parkinsonian actions.

Administration of a 5-HT1A Agonist Synergizes with a Low Dose DAAgonist.

Animals were unilaterally lesioned with 6-OHDA and allowed to recoverand prescreened with L-DOPA (to assess extent of lesion) as describedpreviously. FIG. 10 depicts the rotational response on day 15 in ratsgiven once daily administration of vehicle+SKF 38393 (0.1, 0.3 or 1.0mg/kg). There is little net contralateral turning by day 15 oftreatment. In contrast, animals receiving once daily R(+)-8-OHDPAT (0.3mg/kg) plus SKF 38393 treatments displayed a significantly greatercontralateral turning response that displayed a dose-dependency withrespect to the dose of SKF administered. These data clearly show theability of a 5-HT1A agonist to synergize with an ineffective dose of aD1 agonist to elicit an anti-parkinsonian response.

Previous Exposure to a DA Agonist or L-DOPA is not Required.

Animals were unilaterally lesioned with 6-OHDA and allowed to recover asdescribed previously. However, these animals were not pre-screened withL-DOPA prior to initiation of drug treatments. FIG. 11 compares therotational response between pre-screened (“primed”) and non-pre-screened(“unprimed”) rats after 15 days of once daily administration ofR(+)-8-OHDPAT (0.3 mg/kg) plus SKF 38393 (0.3 mg/kg). There is nosignificant difference between the groups. These data indicate that themethods and compositions of the present invention comprising combined5-HT1A agonist and D1 agonist therapy will be effective in Parkinson'sdisease patients regardless of whether they have previously receivedtreatment (e.g., DA agonist, L-DOPA or nothing).

Example 4 A Serotonin Agonist Reduces Dyskinetic Behavior Elicited byModerate Doses of Dopamine Agonists

The experiments described in this example were conducted as describedabove. A dyskinesia index for each animal was determined during a 3 hrrotational test. FIG. 5 illustrates that repeated R(+)-8-OHDPATadministration reduced dyskinetic behavior elicited by a moderately highdose of SKF 38393 (3.0 mg/kg). Similarly, FIG. 6 illustrates thatrepeated R(+)-8-OHDPAT administration reduced dyskinetic behaviorelicited by quinpirole (0.05 mg/kg).

Example 5 The Anti-Parkinsonian-Enhancing Effect of R-(+)-8-OHDPAT isMediated by the 5-HT1A Receptor

The methods described in the previous examples were used to examine theeffects of a selective 5-HT1A antagonist (WAY 100635) on the enhancedanti-parkinsonian action of a treatment regimen employing bothR(+)-8-OHDPAT and SKF 38393. All animals received at least 14 days ofdaily R(+)-8-OHDPAT. FIG. 7 illustrates that pretreatment of animals ontest day with WAY 100635 (0.1 mg/kg) prior to receiving R(+)-8-OHDPAT(0.3 mg/kg) plus SKF 38393 (0.3 mg/kg) blocked the facilitating effectsof R(+)-8-OHDPAT on the anti-parkinsonian action of SKF 38393. Thesedata confirm that the facilitating action of R(+)-8-OHDPAT is 5-HT1Areceptor-mediated. Nonetheless, knowledge of the mechanism(s) is notnecessary in order to make and use the present invention.

Example 6 Effects of Drug Treatment on Striatal Signaling

Transcription factors play a major role in mediating the long-termeffects of synaptic plasticity by altering the expression ofsynapse-associated proteins. ΔFosB is a truncated splice variant of FosBthat represents a long-lived transcription factor. ΔFosB has been shownto be upregulated following DA denervation in rodent and primate modelsof PD, as well as in PD patients (Cenci et al., Neuroscience,94:515-527, 1999; Perez-Otano et al., Brain Res Mol Brain Res, 53:41-521998; and Tekumalla et al., Biol Psychiatry, 50:813-816, 2001). Repeatedadministration of L-DOPA or a D₁ agonist further elevates striatalΔFosB, while D₂ agonists have no effect (Cenci et al., supra, 1999;Andersson et al., Neurobiol Dis, 6:461-474, 1999; and Doucet et al., EurJ Neurosci, 8:365-385, 1996).

To test whether a drug-related rise in ΔFosB contributes to dyskinesiaselicited by repeated L-DOPA treatment, ΔFosB levels were assessed byimmunoblotting. FIG. 8 provides an image of a typical blot. FIG. 9illustrates that once daily administration of L-DOPA (25 mg/kg plus 6.25mg/kg benserazide) or SKF 38393 (1 mg/kg) for 15 days elicits asignificant increase in ΔFosB in the denervated striatum of unilateral6-OHDA-lesioned rats (*, significantly greater than vehicle-treated;p<0.05). This figure also demonstrates that concomitant administrationof the 5-HT1A agonist R(+)-8-OHDPAT (0.3 mg/kg) with SKF 38393 preventsthe D1 agonist-induced rise in ΔFosB (#, significantly less thanVEH+SKF; p<0.05 and not significantly different from vehicle-treated).Thus a significant target of the treatments of the present invention iscontemplated to be ΔFosB in the striatum. Even so, knowledge of themechanism(s) is not necessary in order to make and use the presentinvention.

Example 7 A Serotonin Agonist Enhances the Anti-Parkinsonian Actions ofDopamine Agonists in a Marmoset Model of Parkinson's Disease

This example describes testing a serotonin agonist with a dopamineagonist in a nonhuman primate model of Parkinson's disease. Briefly,adult common marmosets (Callithrix jacchus) received either 0.9% salineSC (1 ml/kg) daily for five consecutive days (naïve controls) or MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride) SC (2mg/kg) daily for five consecutive days. MPTP administration induces amotor disorder characterized by akinesia, bradykinesia and rigidity,which is relatively stable after an initial recovery period. Abnormalposture, loss of vocalization, diminished blinking, incoordination and atremor are also frequently observed.

Efficacy of administration of a serotonin type 1A receptor agonist and adopamine receptor agonist in reducing at least one symptom ofMPTP-induced motor disorder is measured by behavioral assessment asdescribed (Pearce et al., Psychopharmacol, 142:51-60, 1999). Briefly,automated locomotor counts, behavioral observation and dyskinesiascoring are recorded. Automated locomotor counts are taken through theuse of cages equipped with multiple infrared photocells. The number oflight beam interruptions caused by movement is enumerated in 10-minintervals over a 2-12 h and recorded by computer. An initial period of30-60 min is used for habituation to the cages prior to drug dosing andbehavioral assessment. The animals are also closely monitored by trainedobservers (e.g., a clinical neurologist with experience in movementdisorders). The degree of motor dysfunction is scored on a disabilitygrading system; alertness (normal/0, abnormal/1); reaction to stimuli(normal/0, reduced/1, slow/2, absent/3); blinking (normal/0,abnormal/1); checking movements (present/0, reduced/1, absent/2);posture (normal/0, abnormal trunk/+1, tail/+1, limbs/+1, grosslyabnormal/4); balance (normal/0, unstable/1, spontaneous falls/2);motility (normal/0, mild slowing/1, moderate bradykinesia/2,akinesia/3); vocalisation (normal/0, reduced/1, absent/2); tremor(absent/0, present/1) fur condition (normal/0, dirty/1). These valuesare summed to yield a disability score out of 20. Disability scores aregenerated from continuous observation at half hour intervals before andduring peak drug effect.

Abnormal movements are described according to classically definedcriteria: chorea (rapid random kicking limb movements); athetosis(sinuous writhing limb movements); dystonia (abnormal sustainedposturing); and stereotypy (repetitive purposeless or semipurposivemovement). The presence of dyskinesias is scored at maximum drug effectemploying a dyskinesia scoring system: 0=absent; 1=mild (fleeting andrare dyskinetic postures and movements); 2=moderate (more prominentabnormal movements, but not interfering significantly with normalbehavior); 3=marked (frequent and at times continuous dyskinesiasintruding upon normal repertory of activity); and 4=severe (virtuallycontinuous dyskinetic activity, impairing the animal's normal behavior).

The inventors contemplate that administration of a serotonin receptortype 1A receptor agonist with a low-dose dopamine receptor agonistreduces motor dysfunction (reduces parkinsonian symptoms and/ordopamine-replacement therapy-induced dyskinesias) in MPTP-lesionedmarmosets.

Example 8 A Serotonin Agonist Enhances the Anti-Parkinsonian Actions ofDopamine Agonists in a Parkinson's Disease Patients

This example describes testing a serotonin agonist with a dopamineagonist in a human Parkinson's disease patients. Briefly, all patientsadmitted to this study are diagnosed with idiopathic Parkinson's disease(See, e.g., Gibb and Lees, J Neurol Neurosurg Psychiatry, 51:745-752,1988).

Efficacy of administration of a serotonin type 1A receptor agonist and adopamine receptor agonist in reducing at least one symptom ofParkinson's disease is measured using the United Parkinson's DiseaseRating Scale (Fahn et al. (eds.), Recent Developments in Parkinson'sDisease, vol. 2, New York, N.Y.: Macmillan Publishing Co. Inc., pp.153-163 and 293-304, 1987), whereas dyskinesias are assessed using anart recognized severity scale (Marconi et al., Mov Disord, 9:2-12,1994). Briefly, the dyskinesia severity scale rates abnormal movementsfrom 0 (none) to 4 (severe with markedly impaired function) in sixdifferent parts of the body (face, neck and trunk, and four limbs).

The inventors contemplate that administration of a serotonin receptortype 1A receptor agonist with a low-dose dopamine receptor agonistreduces motor dysfunction (reduces parkinsonian symptoms and/ordopamine-replacement therapy-induced dyskinesias) in human Parkinson'sdisease patients.

All publications and patents mentioned in the above specification areherein incorporated by reference. Various modifications and variationsof the described method and system of the invention will be apparent tothose skilled in the art without departing from the scope and spirit ofthe invention. Although the invention has been described in connectionwith specific preferred embodiments, it should be understood that theinvention as claimed should not be unduly limited to such specificembodiments. Indeed, various modifications of the described modes forcarrying out the invention, which are obvious to those skilled in therelevant fields, are intended to be within the scope of the followingclaims.

We claim:
 1. A method of treating a motor disorder side effectassociated with administration of L-DOPA to a subject having Parkinson'sdisease, wherein said motor disorder side effect is reduced byadministering a therapeutic dose of eltoprazine to said subject.
 2. Themethod according to claim 1, wherein said motor disorder side effect isdyskinesia.
 3. The method according to claim 1, wherein said L-DOPA isadministered at a subtherapeutic dose.
 4. The method according to claim1, wherein said eltoprazine and said L-DOPA are concurrently active insaid subject.
 5. The method according to claim 1, wherein saideltoprazine is administered to said subject after the development ofsaid motor disorder side effect.
 6. The method according to claim 1,wherein said eltoprazine is administered to said subject before thedevelopment of said motor disorder side effect.
 7. The method accordingto claim 1, wherein said eltoprazine is administered to said subjectbefore the initiation of L-DOPA administration.
 8. The method accordingto claim 1, wherein after the administration to said subject of saideltoprazine and said L-DOPA, the dose of L-DOPA is reduced.
 9. Themethod according to claim 1, wherein said subject is a human.
 10. Amethod of treating dyskinesia associated with administration of L-DOPAto a human having Parkinson's disease, wherein said dyskinesia isreduced by administering a therapeutic dose of eltoprazine to saidhuman.
 11. A kit comprising eltoprazine, L-DOPA, and instructions foradministering eltoprazine and L-DOPA to a subject having Parkinson'sdisease.
 12. A method of treating Parkinson's disease in a subject inneed thereof, comprising administering a therapeutic dose of L-DOPA anda therapeutic dose of eltoprazine to said subject.
 13. The methodaccording to claim 12, wherein said L-DOPA is administered at asubtherapeutic dose.
 14. The method according to claim 12, wherein saideltoprazine and said L-DOPA are concurrently active in said subject. 15.The method according to claim 12, wherein said eltoprazine isadministered to said subject before said subject develops dyskinesiaassociated with said L-DOPA administration.
 16. The method according toclaim 12, wherein said eltoprazine is administered to said subject aftersaid subject develops dyskinesia associated with said L-DOPAadministration.
 17. The method according to claim 12, wherein saideltoprazine is administered to said subject before the initiation ofL-DOPA administration.
 18. The method according to claim 12, whereinsaid L-DOPA is administered to said subject before the initiation ofeltoprazine administration.
 19. The method according to claim 12,wherein after the administration to said subject of said eltoprazine andsaid L-DOPA, the dose of L-DOPA is reduced.
 20. The method according toclaim 12, wherein said subject is a human.
 21. A method of treatingParkinson's disease in a human, comprising administering a therapeuticdose of L-DOPA and a therapeutic dose of eltoprazine to said human.